Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

Hashimoto, Yuichi; Chiba, Tomohiro; Yamada, Marina; Nawa, Mikiro; Kanekura, Kohsuke; Suzuki, Hiroaki; Terashita, Kenzo; Aiso, Sadakazu; Nishimoto, Ikuo; Matsuoka, Masao

doi:10.1128/mcb.25.21.9304-9317.2005

Cited by 52 publications

(64 citation statements)

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“…In addition, p75NTR and/or PLAIDD, putative cell membrane receptors for Aâ, are able to cause neuronal cell death when ectopically overexpressed (18,44). We have recently demonstrated that TGF â2 is a natural ligand for amyloid-precursor protein (APP) that activates a neuronal cell death signal cascade (20). Based on of this finding and of the reported observation that TGF â2 expression is upregulated by toxic Aâ (21), we have put forward a new paradigm for neuronal cell death relevant to AD.…”

Section: Neuronal-death Mechanismsmentioning

confidence: 99%

Humanin and Colivelin: Neuronal‐Death‐Suppressing Peptides for Alzheimer's Disease and Amyotrophic Lateral Sclerosis

et al. 2006

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Humanin (HN), a 24-amino-acid neuroprotective peptide, was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient. HN inhibits neuronal death by binding to its specific receptor on the cell membrane and triggering a Jak2/STAT3 prosurvival pathway. The activation of this pathway may represent a therapeutic approach to AD. HN also exhibits neuroprotective activity against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant superoxide dismutase (SOD1). Recent investigations established that AGA-(C8R)-HNG17, a 17-amno-acid derivative of HN, is 10 5 times more potent as a neuroprotective than HN; at 10-picomolar and higher concentrations in vitro it completely suppresses neuronal death. Moreover, a 26-aminoacid peptide colivelin (CL), composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)-HNG17, provides complete neuroprotection at 100-femtomolar or higher concentrations in vitro. A series of experiments using mouse AD and ALS models further established the efficacy of HN derivatives, including CL, against these diseases in vivo. HN and CL can be viewed as drug candidates for neuronal death suppression therapy in AD or ALS.

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Section: Neuronal-death Mechanismsmentioning

confidence: 99%

Humanin and Colivelin: Neuronal‐Death‐Suppressing Peptides for Alzheimer's Disease and Amyotrophic Lateral Sclerosis

et al. 2006

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“…The mNetrin1 cDNA was inserted into the pEF1/MycHis vector (Invitrogen) at the EcoRI and XbaI sites. Mouse WT-APP and V642I-APP cDNAs inserted in the pcDNA3.1/MycHis were described previously (11)(12)(13). The expression vectors for dominant-negative ASK1 and JNK were also described in earlier studies (11)(12)(13).…”

Section: Methodsmentioning

confidence: 99%

“…Cells, Cell Death, and Cell Viability-Neuronal cell death assays related to AD were first performed by Yamatsuji et al (10) and previously described in detail (11)(12)(13)21). Neurohybrid F11 cells were also described earlier (22).…”

Section: Methodsmentioning

confidence: 99%

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An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

Hashimoto¹,

Toyama²,

Kusakari³

et al. 2016

Journal of Biological Chemistry

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A missense mutation (T835M) in the uncoordinated-5C (UNC5C) netrin receptor gene increases the risk of late-onset Alzheimer disease (AD) and also the vulnerability of neurons harboring the mutation to various insults. The molecular mechanisms underlying T835M-UNC5C-induced death remain to be elucidated. In this study, we show that overexpression of wildtype UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M. An AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1, inhibit this death. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of death-associated protein kinase 1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/ JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ␤ precursor protein (APP). Notably, netrin1 also binds to APP and partially inhibits the death-signaling cascade, induced by APP. These results may provide new insight into the amyloid ␤-independent pathomechanism of AD.

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“…The data suggest a scenario in which C31, when removed from APP, abnormally activates or disrupts signaling pathways mediated by APP. One possibility is that the signaling initiated by interaction of the APP C-terminal domain with signal transduction proteins normally is tightly regulated by binding of ligand(s) to its extracellular domain (variously identified as F-spondin [29], Notch [30,31], TGF-β2 [32], and even Aβ [33,34]). In such a scenario, as suggested by McPhie et al, C31, when not attached to APP, is relieved of the normal constraints imposed on it when the extracellular domain of APP is not occupied by a ligand, and becomes constitutively active or else takes on signaling functions that it does not normally possess.…”

Section: Referencementioning

confidence: 99%

Alzheimer Research Forum Discussion: Gain or Loss of Function – Time to Shake up Assumptions on γ-Secretase in Alzheimer Disease?

2007

JAD

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A number of mutations in presenilin (PS) 1, 2, or APP genes linked to familial AD (FAD) have been 402 Alzheimer Research Forum Discussion: Gain or Loss of Functionshown to increase the ratio of Aβ42/Aβ40 secreted from cells, or in the brains of transgenic mice overexpressing these mutant genes. As pointed out by Bentahir et al. and Kumar-Singh et al., the absolute levels of secreted Aβ40 are often significantly decreased, while those of Aβ42 are not robustly changed, resulting in an increase in the Aβ42/Aβ40 ratio.γ-secretase cleaves its substrates at multiple sites within the transmembrane domain; the γ-cleavages of APP take place at positions 40 or 42, and the γ or ε-cleavage to produce AICD at position 49. The catalytic site of γ-secretase comprising the two transmembrane aspartate residues appears to attack the scissile bonds of substrates (which are predicted to form α-helices) at a combination of multiple sites. This determines the levels of products and their relative ratios at a constant level, that is, ε-cleavage to produce AICD at position 49 and γ-cleavage to yield Aβ40 being predominant. FAD mutations cause substitutions of single amino acid residues within PS polypeptide, and these substitutions shift the preferred cleavage sites from positions 40 and 49 to 42, facilitating production of a more aggregable Aβ42 species. The precise molecular mechanism whereby FAD mutations cause the "shift" in the cleavage sites by γ-secretase remains unclear, but single amino acid substitutions in PS may subtly distort its three-dimensional structure and alter the cleavage patterns.It is currently unknown whether reduction in Aβ40 cleavage either increases the supply of substrates to the γ42-secretase within an identical protease complex or to a subcellular compartment that preferentially produces Aβ42, or whether, alternatively, all the changes take place simultaneously. In this regard, the pathological phenotype caused by FAD mutations, that is, increase in Aβ42 and decrease in Aβ40, could well be interpreted either as "gain of abnormal function" that alters the function of PS (as γ-secretase), or alternatively as "partial loss of function" when we consider the production of the major cleavage products, that is, Aβ40 or AICD, as its "normal" function.Which, then, is the pathogenic phenomenon in the brains of patients with AD, especially FAD with a PS mutation: reduction in Aβ40, reduction in AICD, or increase in Aβ42? We have to keep in mind that earlyonset FAD is an autosomal-dominant disease, in which patients harbor one mutant allele together with one wild-type (wt) allele. Indeed, heterozygous PS1 KO mice that carry one copy of wt PS1, or knock-in mice that harbor one copy each of mutant and wt PS1 (Wang R et al., J Biol Chem, in press) showed only a moderate decrease in γ-secretase activity and Aβ40 level compared to those with only one copy of mutant PS1. Moreover, FAD patients do not show any developmental abnormalities caused by decreased Notch signaling. Collectively, the levels of Aβ40 or AICD/NICD p...

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Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

Cited by 52 publications

References 53 publications

Humanin and Colivelin: Neuronal‐Death‐Suppressing Peptides for Alzheimer's Disease and Amyotrophic Lateral Sclerosis

Humanin and Colivelin: Neuronal‐Death‐Suppressing Peptides for Alzheimer's Disease and Amyotrophic Lateral Sclerosis

An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

Alzheimer Research Forum Discussion: Gain or Loss of Function – Time to Shake up Assumptions on γ-Secretase in Alzheimer Disease?

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